19-10351837-C-T

Variant names:

• chr19-10351837-C-T
• rs11085725
• NM_003331.5:c.3318+597G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003331.5(TYK2):​c.3318+597G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 151,710 control chromosomes in the GnomAD database, including 5,270 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.24 (5270 hom., cov: 30)
• Consequence: TYK2 NM_003331.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.813
• Publications: 20 publications found

Genes affected

TYK2 (HGNC:12440): (tyrosine kinase 2) This gene encodes a member of the tyrosine kinase and, more specifically, the Janus kinases (JAKs) protein families. This protein associates with the cytoplasmic domain of type I and type II cytokine receptors and promulgate cytokine signals by phosphorylating receptor subunits. It is also a component of both the type I and type III interferon signaling pathways. As such, it may play a role in anti-viral immunity. A mutation in this gene has been associated with Immunodeficiency 35. [provided by RefSeq, Sep 2020]

TYK2 Gene-Disease associations (from GenCC):

• immunodeficiency 35

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYK2	NM_003331.5	c.3318+597G>A		intron_variant	Intron 23 of 24	ENST00000525621.6	NP_003322.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYK2	ENST00000525621.6	c.3318+597G>A		intron_variant	Intron 23 of 24	1	NM_003331.5	ENSP00000431885.1

Frequencies

GnomAD3 genomes AF: 0.244 AC: 36953 AN: 151592 Hom.: 5260 Cov.: 30

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.250

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.244 AC: 36977 AN: 151710 Hom.: 5270 Cov.: 30 AF XY: 0.244 AC XY: 18095 AN XY: 74104

African (AFR) AF: 0.113 AC: 4664 AN: 41444

American (AMR) AF: 0.286 AC: 4337 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1117 AN: 3464

East Asian (EAS) AF: 0.554 AC: 2819 AN: 5086

South Asian (SAS) AF: 0.281 AC: 1347 AN: 4798

European-Finnish (FIN) AF: 0.242 AC: 2545 AN: 10528

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.282 AC: 19163 AN: 67892

Other (OTH) AF: 0.249 AC: 525 AN: 2110

Alfa AF: 0.256 Hom.: 673

Bravo AF: 0.245

Asia WGS AF: 0.349 AC: 1212 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.84
DANN	Benign	0.49
PhyloP100		-0.81
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11085725; hg19: chr19-10462513;